1. Field of the Invention
This invention relates to certain novel bicyclic benzo fused compounds, more particularly to certain 5-hydroxy-7-substituted-3,4-dihydro-2H-benzopyrans which are also substituted at the 3-position or the 4-position, the corresponding tetrahydroquinoline and tetralin analogs and derivatives thereof and pharmaceutically acceptable cationic and acid addition salts thereof, useful as CNS agents, especially as analgesic, antidiarrheals, and antiemetic agents for use in mammals, including man; methods for their use and pharmaceutical compositions containing them.
2. Description of the Prior Art
Despite the current availability of a number of analgesic agents, the search for new and improved agents continues, thus pointing to the lack of an agent useful for the control of broad levels of pain and accompanied by a minimum of side-effects. The most commonly used agent, aspirin, is of no practical value for the control of severe pain and is known to exhibit various undesirable side-effects. Other, more potent analgesics such as d-propoxyphene, codeine, and morphine, possess addictive liability. The need for improved and potent analgesics is, therefore, evident.
A series of analgesic dibenzo[b,d]pyrans, having at the 9-position substituents such as alkyl, hydroxy and oxo, are disclosed in U.S. Pat. Nos. 3,507,885; 3,636,058; 3,649,650; 3,856,821; 3,928,598; 3,944,673, 3,953,603 and 4,143,139. Particularly of interest is d1-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hex ahydro-9H-dibenzo[b,d]pyran-9-one, an antiemetic, antianxiety agent with analgesic properties in animals, now generally referred to as nabilone.
U.S. Pat. No. 4,152,450 discloses certain 3-alkyl-1-hydroxytetrahydro and hexahydrodibenzo[b,d]pyrans, having an amino or amido group at the 9-position, which are useful as analgesics, antidepressants, antianxiety agents and hypotensive agents.
U.S. Pat. No. 4,188,495 discloses analgesic 1,9-dihydroxyoctahydrophenanthrenes, 1-hydroxyoctahydrophenanthren-9-ones and derivatives thereof of the formula ##STR4## where X.sub.9 is CHOH or C.dbd.O, M.sub.3 is CH.sub.2 and R.sub.1, R.sub.4, R.sub.5, Z and W are as defined above.
U.S. Pat. No. 4,260,764, issued Apr. 7, 1981, discloses compounds of the above formula wherein M.sub.3 is NR.sub.6 and X.sub.9, R.sub.1, R.sub.4, R.sub.5, R.sub.6, Z and W are as defined above. They are useful as analgesics, tranquilizers, hypotensives, diuretics and as agents for treatment of glaucoma. U.S. Pat. No. 4,228,169, issued Oct. 14, 1980, discloses the same compounds to be useful as antiemetic agents.
Bergel et al., J. Chem. Soc., 286 (1943) investigated the replacement of the pentyl group at the 3-position of 7,8,9,10-tetrahydro-3-pentyl-6,6,9-trimethyl-6H-dibenzo[b,d]pyran-1-ol by alkoxy groups of four to eight carbon atoms and found that these compounds had little or no hashish activity at 10 to 20 mg/kg.
In a more recent study, Loev et al., J. Med. Chem., 16, 1200-1206 (1973) report a comparison of 7,8,9,10-tetrahydro-3-substituted-6,6,9-trimethyl-6H-dibenzo[b,d]-pyran-1- ols in which the 3-substituent is --OCH(CH.sub.3)C.sub.5 H.sub.11 ; --CH.sub.2 CH(CH.sub.3)C.sub.5 H.sub.11 ; or --CH(CH.sub.3)C.sub.5 H.sub.11. The ether side chain containing compound was 50% less active in central nervous system activity than the corresponding compound in which the alkyl side chain is directly attached to the aromatic ring, rather than through an intervening oxygen atom; and 5 times as active as the compound in which oxygen is replaced by methylene.
Mechoulam and Edery in "Marijuana", edited by Mechoulam, Academic Press, New York, 1973, page 127, observe that major structural changes in the tetrahydrocannabinol molecule seem to result in steep reductions in analgesic activity.
U.S. Pat. No. 4,087,545 discloses the antiemetic and antinausea properties of 1-hydroxy-3-alkyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-ones.
Sallan et al., N.E.J. Med. 293, 795 (1975) reported oral delta-9-tetrahydrocannabinol has antiemetic properties in patients receiving cancer chemotherapy.
Delta-9-tetrahydrocannibinol is reported by Shannon et al. (Life Sciences 23, 49-54, 1978) to lack antiemetic effects in apomorphine-induced emesis in the dog. Borison et al., N. England J. of Med. 298, 1480 (1978) report the use of unanesthetized cats as an animal model for determining the antiemetic effect of compounds especially in connection with emesis induced by cancer chemotherapy drugs. They found that pretreatment of unanesthetized cats with 1-hydroxy-3-(1',1'-dimethylheptyl)-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro- 9H-dibenzo[b,d]pyran-9(8H)-one (nabilone) affords pronounced protection against vomiting per se after injection of antineoplastic drugs.
Starting materials of the formulae below, useful for preparation of the invention compounds of formula (I) are known in the art. ##STR5## where R.sub.1, R.sub.4, R.sub.5, M, Z and W are as defined above. Detailed procedures for the preparation of said starting compounds wherein M is O are set forth in U.S. Pat. No. 4,143,139, issued Mar. 6, 1979 and U.S. Pat. No. 4,235,913, issued Nov. 25, 1980, each of which is hereby incorporated by reference. Similarly, detailed procedures for preparation of the above starting materials wherein M is CH.sub.2 are set forth in U.S. Pat. No. 4,188,495, issued Feb. 12, 1980; and wherein M is NR.sub.6, and R.sub.6 is as defined herein are set forth in U.S. Pat. No. 4,228,169, issued Oct. 14, 1980, and U.S. Pat. No. 4,260,764, issued Apr. 7, 1981, each of which are also hereby incorporated by reference.